PROJECT SUMMARY The nervous system is endowed with potent and adaptive mechanisms that maintain stable activity despite the changes that occur during early development, growth, experience, and aging of the brain. These homeostatic properties are thought to ensure robust and reliable functionality of neurons, synapses, and neural circuits. We have pioneered forward genetic screens using electrophysiology at the Drosophila neuromuscular junction (NMJ) to reveal new genes and mechanisms that regulate the homeostatic control of synaptic strength. This fundamental form of synaptic plasticity is conserved in flies, mice, and humans, yet genes and mechanisms involved remain enigmatic. In a new electrophysiology-based forward genetic screen for genes required for synaptic homeostasis, we have identified the Drosophila homolog of the human Survival of Motor Neuron (SMN) gene. SMN mutations in humans cause Spinal Muscular Atrophy (SMA), a devastating NMJ disease that is the leading genetic cause of death in infants. SMA is a neurological disease characterized by loss of NMJ function, ultimately leading to muscle weakness and atrophy. The Drosophila SMN gene is highly homologous to human SMN1, and remarkably, Drosophila SMN mutants exhibit phenotypes that parallels those observed in the human disease, including muscle atrophy, motor rhythm abnormalities, and lethality. This proposal will first test the hypothesis that loss of SMN results in reduced excitatory synaptic drive onto motor neurons from cholinergic neurons in the motor circuit, revealing a novel mechanism that may induce homeostatic signaling at the NMJ. Second, because SMN is involved in RNA splicing and metabolism, we will leverage a powerful tissue-specific ribosome profiling approach we have developed to identify the key targets of SMN, in genetically defined cell types, that support normal synaptic and motor circuit function.